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J. Biol. Chem., Vol. 281, Issue 18, 12799-12808, May 5, 2006

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24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux^*

Karlygash Abildayeva, Paula J. Jansen, Veronica Hirsch-Reinshagen¹, Vincent W. Bloks^¶, Arjen H. F. Bakker^||, Frans C. S. Ramaekers, Jan de Vente, Albert K. Groen, Cheryl L. Wellington,¹², Folkert Kuipers^¶, and Monique Mulder³

From the Department of Molecular Cell Biology, Institute of Brain and Behavior (European Graduate School of Neuroscience, EURON), Department of Psychiatry and Neuropsychology, and ^||Department of Molecular Genetics, University of Maastricht, 6200 MD Maastricht, The Netherlands, Department of Pathology and Laboratory Medicine, British Columbia Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada, ^¶Department of Pediatrics, University Medical Center, 9713 GZ Groningen, The Netherlands, and Department of Medical Biochemistry, Academic Medical Center, 1105 BK Amsterdam, The Netherlands

Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXR and - expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.

Received for publication, February 2, 2006

^* This work was supported in part by the Internationale Stichting Alzheimer Onderzoek Grant 03516 and in part by Netherlands Brain Foundation Grant H00.15. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Canadian Institutes of Health Research.

² Supported by the Alzheimer Society of Canada.

³ To whom correspondence should be addressed: Dept. of Molecular Cell Biology (box 17), University of Maastricht, P. O. Box 616, 6200 MD Maastricht, The Netherlands. Tel.: 31-43-3881425; Fax: 31-43-3884151; E-mail: M.Mulder{at}MOLCELB.unimaas.nl.

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